Control of cancer is a most important subject in today's medicine, and new cancer therapy and new anti-cancer agents are topics of the greatest interest among medical and pharmaceutical researchers. At the present time, the number one cause of death in Japan is the cancer, and many new patients are found every year.
As anti-cancer agents used in chemotherapy, aside from the conventional alkylating agents, metabolic antagonists, and antibiotics, microorganism-derived bioreactive modification substances represented by Picibanil (trade name of Chugai Pharmaceutical, Japan) and Krestin (trade name of Sankyo Pharmaceutical, Japan) once flourished. Existing compounds such as alkylating agents originally made use of cytotoxicity, and the uses were considerably limited owing to manifest side effects, but Picibanil and other later bioreactive modification substances have actions of enhancing the immune function of the body and expel cancer cells. However, as their limits have come to be known, attention has been turned to bio-active proteins derived from higher animals such as interferon, interleukin 2, and TNF (tumor necrosis factor). Yet, their action spectra were actually by far broader than initially estimated, and the belief that they were free from side effects was lost.
In this background, it is at least true that the treatment of cancer is changing its direction, that is, from the conventional evaluation of mere fighting against the cancer focus to the concept considering “quality of life” to evaluate the treatment in the process of improvement of total function of the body, and HGF discovered by the present inventor has been already reported that it is an active ingredient for anti-cancer agent (Japanese Laid-open Patent No. 6-25010).
As mentioned above, the existing anti-cancer agents are far from a decisive remedy in consideration of the side effects and doubts about the anti-cancer action itself, and the bio-active proteins of the next generation are mainly factors relating to the immune system as far as developed in the past, and are not always expected to be used widely as ultimate anti-cancer agents. Accordingly, among the bioactive proteins produced in the body, in particular, among those definite in physiological action and researched sufficiently of the spectrum of activity, it is required to discover a true anti-cancer agent. Especially, since the bioactive proteins, interferons and interleukins developed so far are mostly factors relating to the immune system, biological factors having a completely different action seems to be important as a future anti-cancer agent.
In Japan, cancer is the number 1 cause of death as mentioned above, but it may be dared to say that its risk depends on invasion and metastasis of cancer cells. Several growth factors have been reported to be related to the ability of invasion and metastasis of cancer cells, and recently HGF has been disclosed to be a strong factor for inducing invasion and metastasis ability to various cancer cells (H. Shimura et al., J. Jap. Cancer Res. 86, 662-669, 1995). Actually, the invasion ability of lung cancer and gallbladder cancer known to be extremely high in malignancy has been confirmed to be induced depending on HGF, and HGF level in the primary tissues of lung cancer is known to be a risk factor closely correlated with the malignancy and mortality of lung cancer.
HGF is a protein which has been discovered as a factor for proliferating liver parenchymal cells in vitro (Biochem Biophys Res Commun, 122, 1450, 1984; Proc. Natl. Acad. Sci. USA, 83, 6489, 1986; FEBS Letter, 22, 311, 1987; Nature, 342, 440, 1989; Proc. Natl. Acad. Sci. USA, 87, 3200, 1990). This HGF first discovered as a factor for specifically proliferating liver parenchymal cells has been shown to have various activities in the body such as tissue wound healing as a result of recent studies by the present inventor and many other researchers, and it is highly expected to be applied into remedies in humans and animals, as well as the subject of study. Concerning a receptor of such HGF, the recent studies unveiled that the c-Met proto oncogene codes HGF receptor (Bottaro et al., Science, 251, 802-804, 1991; Naldini et al., Oncogene, 6, 501-504, 1991).
It is thus clarified that HGF is a factor for powerfully inducing invasion and metastasis ability to various cancer cells, and development of antagonist and inhibitor for specifically blocking the invasion and metastasis ability of cancer cells by HGF seems to be an extremely important subject of study from the viewpoint of control of cancer.